The applicant is a clinical molecular geneticist who is eligible for ABMG-accredited certification in the Clinical Molecular Genetics program. His long-term objective is to become an independent physician- scientist focused on studying the genetic bases of male infertility that affects the reproductive health of men. This proposal will provide the applicant with training in reproductive biology and new technologies in human and mouse genetics. The overall scientific goal of this project is to identify and characterize mutations in male infertility- associated genes that result in oligozoospermia (OS). Male infertility affects nearly 4,000,000 men in the USA, of which at least 25% are diagnosed as idiopathic. An etiology of male infertility is often associated with abnormal semen characteristics (i.e., sperm concentration, motility, morphology, etc.). Oligozoospermia is the most common semen abnormality observed among infertile males. The Specific Aims of the proposed study are: 1) Develop cDNA and DNA collections of oligozoospermic semen samples; 2) Study candidate genes for OS-associated mutations by direct cDNA sequencing and in vitro functional assays; 3) Identify and map genomic aberrations associated with severe OS, using oligo microarray comparative genome hybridization (CGH) technology; and 4) Characterize the CGH-detected gene-candidate that is associated with OS, using mouse knockout or knock-in models. The selection of OS-associated candidate genes will be prioritized according to their protein functional evidence and the gene's position in altered chromosome region. The applicant will study mutations and genomic abnormalities in cDNA and DNA samples from oligozoospermic patients, using cDNA sequencing approach and comprehensive genome-wide CGH microarray. A mutant mouse model will be developed in attempt to mimic the most common form of semen abnormality, oligozoospermia in human. The candidate will characterize the mutant mice by determining the spatiotemporal effects of gene ablation on spermatogenesis and fertilization. Identification and characterization specific gene mutations that associate with oligozoospermia will lead to the development of novel diagnostic procedures, and will help with prognosis in assisted reproductive medicine. Ultimately, it will provide insight into the molecular basis of male infertility, and eventually may facilitate the creation of non-hormonal contraceptives. Proposed study will be performed in an environment known for its collaborative studies in human and mouse genetics. The long-term career goals of the applicant is to become an independent physician-scientist focused on studying genetic disorders that affect male reproductive system. PUBLIC HEALTH RELEVANCE: Male infertility associated with low sperm count (oligozoospermia) affects nearly 2% of men worldwide. The genetic defects that cause this type of male infertility are largely unknown, preventing effective prognosis and treatment of these infertile men. The present research proposal aims to determine the genetic defects that cause male infertility, using the novel approach pioneered in our laboratory.